DNA Polymerase Zeta Inactivation in Prostate Cancer
Abstract
Rationale of the Application: Not all prostate cancer patients respond in the same way to therapies. For example, some cancers respond well to hormone therapies and others to radiation therapy. A major reason for these differences is that different genetic changes underlie individual cancers. In order to personalize therapy and make it much more effective, it is important to take advantage of genetic analyses and determine, as early as possible during treatment, the therapeutic strategies that will be most effective to cure or control the cancer. Although it is the most common cancer in American men, more than a quarter of primary prostate cancers of both good and poor clinical prognosis are driven by unknown molecular changes in the genome. Recently, in the course of our studies of DNA repair, we analyzed prostate cancer genome data and discovered that the gene for an important DNA repair enzyme called DNA polymerase zeta (abbreviated "pol zeta") is deleted in 13% of primary prostate cancers. This is very significant because identification of cancers with deletion of the pol zeta gene is highly likely to be useful in diagnosis and therapy. This is because suppressing pol zeta sensitizes cells to DNA damage. The absence of pol zeta is likely very important for improving therapy in these cancers, but it has never been investigated. The Objective: The major objective of the research is to develop the idea that prostate cancers with pol zeta deletions are specifically sensitive to therapeutic DNA damaging agents, including radiation. This could lead to individualized treatment of an important group of prostate cancers. It will also open up the usefulness of DNA damaging chemotherapy for a previously unrecognized major group of prostate cancers. Because we know that normal cells do not grow well in the absence of pol zeta, we also intend in this research to identify genetic alterations that allow cells to proliferate in the absence of pol zeta. This will be a practically important advance because it will help identify the pol zeta-deleted class of cancers. The Research Aims: It is an exciting prospect that pol zeta loss represents a previously unrecognized genetic alteration in human prostate cancer. However, several gaps in knowledge exist. We will fill these gaps by (1) determining whether pol zeta-defective prostate cancer cells are indeed more sensitive than normal cells to DNA damaging agents and (2) determining gene changes that allow tumors able to proliferate in the absence of pol zeta. We propose a strategy to identify candidate genes that may be altered. Our research group is uniquely positioned to carry out this research, as we have developed the necessary specialized tools and approaches to make it feasible. These include genetically engineered mouse and human cell models in which pol zeta has been deleted. Contributions to Advancing the Field of Prostate Cancer Research: This research addresses the Prostate Cancer Research Program Overarching Challenge for 2016, "Develop strategies to prevent progression to lethal prostate cancer." The ideas to be developed here should lead to individualized radiation treatment of an important group of primary prostate cancers. They will also expand the possibility of using DNA damaging chemotherapy for a significant fraction of mutagen-sensitive prostate cancers. The research will further identify genetic alterations that allow cells to proliferate in the absence of pol zeta. This will be an important advance, facilitating diagnosis of the pol zeta-deleted class of cancers and earmarking this group of cancers for specialized radiation or chemotherapy. Clinical Applicability and Timeline: This research will provide a direct means to select patients that are likely to respond best to radiation or chemotherapy treatments. This will encompass an estimated 13% of all primary prostate cancer patients (including those with advanced diagnosis) and w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710239
Entities
People
- Richard D. Wood
Organizations
- United States Army
- University of Texas at Austin